JPH07138248A - Ester compound from retinoid and ascorbic acid and derivative therefrom and their production - Google Patents

Abstract

PURPOSE:To provide a new compound useful as e.g. an antioxidant for foods. CONSTITUTION:The objective compound of formula I [R1 is of formula II (X1 and X2 are each alkyl, hydroxyalkyl or carboxyl), etc.; R2 to R4 are combined into acetal or ketal; n is 1-10], e.g. 3-retinoyl-L-ascorbic acid-5,6-acetonide. The compound of the formula I can be obtained by reaction between a compound of formula III (R5 is halogen, etc.) and a compound of formula IV (R6 is H, alkali metal, etc.).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel compound, an ester compound consisting of retinoid and ascorbic acid, a derivative thereof and a process for producing them.

[0002]

2. Description of the Related Art Various compounds have been reported as derivatives of ascorbic acid and retinoids.
(JP-A-60-130582, JP-A-61-2639
No. 69, The Retinoids Volume 1, 7
Pp. 145 (1984)). However, ester compounds and derivatives of retinoids, which are fat-soluble vitamins, and ascorbic acid, which is a water-soluble vitamin, have not been reported.

[0003]

Retinoids are vitamin A and its related compounds. Vitamin A is a fat-soluble vitamin that has been recognized for its growth in animals, maintenance of normal vision, normal regulation of epithelial tissue differentiation, maintenance of immune system, antitumor effect, and the like. However, since it has a polyene skeleton, it is very sensitive and unstable to air, acid, heat, metal ions, etc. On the other hand, ascorbic acid is vitamin C, which is a water-soluble vitamin, and has a strong reducing power, and it has biosynthesis of collagen, metabolism of tyrosine, biosynthesis of catecholamine,
Detoxification of xenobiotics and involvement of lipid metabolism system are recognized substances. Therefore, an ester compound composed of retinoid and ascorbic acid and its derivative are expected to be substances having both the properties and activities of vitamin A and vitamin C, and further, vitamin A and vitamin C.
It is expected to have a new physiologically active effect that was not observed in.

[0004]

In view of the above circumstances, the present inventors have conducted diligent research, and as a result, succeeded in creating a novel compound, an ester compound consisting of retinoid and ascorbic acid, and a derivative thereof, and the present invention Has been completed. That is, the present invention provides formula (I):

[0005]

[Chemical 7]

[Wherein R ₁ is

[0007]

[Chemical 8]

(X ₁ and X ₂ are the same or different and each represents an alkyl group, a hydroxyalkyl group or a carboxyl group), and R ₂ , R ₃ and R ₄ are the same or different and are hydrogen or organic. Indicates a residue. Also, R
₃ and R ₄ may together form an acetal or ketal. Further, n is 1-10,
[] Includes all stereoisomers. ] Or a salt thereof, (2) a compound or salt thereof according to the above (1), wherein R ₂ , R ₃ and R ₄ are hydrogen, (3)
R ₂ , R ₃ and R ₄ are each an organic residue selected from an optionally substituted alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aralkyl group, aryl group, heterocyclic group or acyl group. The compound or salt thereof described in (1) above, (4) X ₁ and X ₂ are the same or different and each is a methyl group, a hydroxymethyl group or a carboxyl group, or a salt thereof (5) ) R ₁ is

[0009]

[Chemical 9]

The compound or salt thereof described in (1) above, which is a group represented by: (6) the compound or salt thereof described in (1) above, wherein n is 1 to 5, and (7) n is 2. The compound or salt thereof according to (6) above, (8) formula (II): [In the formula, R ₁ has the same meaning as in the general formula (I), R ₅ represents halogen or the formula (III):

[0011]

(X ₅ is an optionally substituted carbon atom 1
4 represents a linear or branched alkyl group. ) Represents a substituent, n is 1 to 10, and the inside of [] includes all stereoisomers. ] And the compound represented by Formula (IV)

[0013]

[Chemical 10]

[In the formula, R ₂ , R ₃ and R ₄ have the same meaning as in the formula (I), and R ₃ and R ₄ may together form an acetal or a ketal. R ₆ represents hydrogen, an alkali metal or an alkaline earth metal. ] The compound (I) characterized by reacting the compound represented by:

[0015]

[Chemical 11]

[Wherein R ₁ is

[0017]

[Chemical 12]

(X ₁ and X ₂ are the same or different and each represents an alkyl group, a hydroxyalkyl group, or a carboxyl group), and R ₂ , R ₃ and R ₄ are the same or different and are hydrogen or an organic group. Indicates a residue. Also, R
₃ and R ₄ may together form an acetal or ketal. Further, n is 1-10,
[] Includes all stereoisomers. ] The manufacturing method of the compound represented by these.

In the formula (I), the organic residue represented by R ₂ , R ₃ and R ₄ is an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aralkyl group, an aryl group, a heterocyclic group or an acyl group. Groups and the like. Each of these groups is halogen (eg, chlorine, bromine, iodine, fluorine, etc.), cyano, hydroxyl, carboxyl or its ester, nitro, aminocarbonyl, C
_1-22 acyl (eg formyl, acetyl, propionyl,
It may have a substituent such as butyryl, stearoyl, oleoyl), C _1-22 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, hexyloxy, etc.) and the like.

The alkyl group exemplified as the organic residue represented by R ₂ , R ₃ and R ₄ is preferably a linear or branched alkyl group having 1 to 22 carbon atoms, more preferably 1 to 22 carbon atoms. 10 are preferred, especially 1 to 5 carbon atoms
Are preferred. Specific examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-amyl, tert.
-Amyl, n-hexyl, n-heptyl, n-octyl, n
-Nonyl, n-decyl, n-undecyl, n-dodecyl, n
-Tridecyl, n-tetradecyl, n-pentadecyl, n
-Hexadecyl, n-heptadecyl, n-octadecyl, n-eicosyl, n-docosyl, n-tetracosyl, n
-Pentacosyl and the like.

The cycloalkyl group exemplified as the organic residue represented by R ₂ , R ₃ and R ₄ has 3 to 10 carbon atoms.
8, preferably 5 to 7. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The alkenyl group exemplified as the organic residue represented by R ₂ , R ₃ and R ₄ has 2 to 2 carbon atoms.
2, preferably 2 to 10. Examples are vinyl, propenyl, butenyl, pentenyl,
Heptenyl, nonyl, undecenyl, tridecenyl, pentadecenyl, heptadecenyl, nonadecenyl, eicosenyl and the like can be mentioned.

The alkynyl group exemplified as the organic residue represented by R ₂ , R ₃ and R ₄ has 2 to 2 carbon atoms.
2, preferably 2 to 10. Specific examples include ethynyl, propynyl, butynyl, hexynyl, octynyl, nonynyl, decynyl, dodecynyl, tetradecynyl, heptadecynyl, octadecynyl, eicodecynyl and the like.

The aralkyl group exemplified as the organic residue represented by R ₂ , R ₃ and R ₄ has 6 to 1 carbon atoms.
4, preferably aryl having 6 to 8 carbon atoms and 1 to carbon atoms
Those having an alkyl group of 6, preferably 1 to 3 are mentioned. Specific examples include benzyl, phenylethyl, methylbenzyl, naphthylmethyl and the like.

The aryl group exemplified as the organic residue represented by R ₂ , R ₃ and R ₄ has 6 to 14 carbon atoms,
Preferred are those having 6 to 8 carbon atoms, specifically phenyl, naphthyl and the like. The aryl group may be substituted, and the substituent is the above-mentioned substituent [that is, halogen (eg, chlorine, bromine, iodine, fluorine, etc.),
Cyano, hydroxyl, carboxyl or its ester, nitro, aminocarbonyl, C _1-22 acyl (eg, formyl, acetyl, propionyl, butyryl, stearoyl, oleoyl etc.), C _1-22 alkoxy (eg, methoxy, ethoxy, propoxy). , Butoxy, hexyloxy, etc.)], for example, selected from the above-mentioned alkyl group, alkenyl group and alkynyl group. The substituent may be at any substitutable position on the ring of the aryl group.

The heterocyclic group exemplified as the organic residue represented by R ₂ , R ₃ and R ₄ is nitrogen as a ring-constituting atom,
It means a 5- to 7-membered ring group containing at least one hetero atom selected from oxygen and sulfur, and includes both aromatic heterocyclic groups and non-aromatic heterocyclic groups. Examples of the aromatic heterocyclic group include pyridyl, tetrazolyl, furyl, thienyl and the like. Examples of the non-aromatic heterocyclic group include tetrahydrofuranyl, dihydropyranyl and the like. The heterocyclic group may be substituted with the same group and position as the above-mentioned substituent of the aryl group.

The acyl group exemplified as the organic residue represented by R ₂ , R ₃ and R ₄ includes those having 1 to 22 carbon atoms, preferably 1 to 8 carbon atoms. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, otakunoyl, nonanoyl, decanoyl, uraloyl, myristoyl, palmitoyl, stearoyl, benzoyl.

Further, R ₃ and R ₄ may together form an acetal residue or a ketal residue.
In this case, R ₃ and R ₄ have the formula (V):

[0029]

[Chemical 13]

[Wherein X ₃ and X ₄ are the same or different and each represents a hydrogen atom, an alkyl group or an optionally substituted phenyl group]. Examples of the alkyl group represented by X ₃ or X ₄ include those similar to the alkyl group represented by R ₂ above. Of these, methyl and ethyl are preferred. Examples of the substituent of the optionally substituted phenyl group represented by X ₃ include the same as the substituents of the aryl group represented by R ₂ . Of these, p
-Methoxy group is preferred. In the present invention, it is preferred that X ₃ and X ₄ are methyl groups.

Further, n is in the range of 1 to 10, preferably 1
Is in the range of to 5, and [] includes all stereoisomers.

The compound represented by the formula (I) of the present invention has the formula (I)
I): [In the formula, R ₁ has the same meaning as in the general formula (I), R ₅ represents halogen (eg, fluorine, chlorine, bromine, iodine) or the formula (II
I):

[0033]

(X ₅ is an optionally substituted carbon atom 1
4 represents a linear or branched alkyl group (eg, methyl group, trifluoromethyl group, ethyl group, etc.). )
Represents a substituent represented by, n is 1 to 10, preferably 1
~ 5, and [] includes all stereoisomers. And a compound represented by the formula (IV)

[0035]

[Chemical 14]

[Wherein R ₂ , R ₃ and R ₄ have the same meaning as in formula (I), and R ₃ and R ₄ together form an acetal or ketal represented by the above formula (V). You may have. R ₆ is hydrogen, an alkali metal (eg, lithium, sodium, potassium, etc.) or an alkaline earth metal (eg,
Magnesium, calcium, etc.). ] It can manufacture by making the compound represented by these react.

The amount of the compound represented by the formula (IV) used is
It is 0.5 equivalents or more, preferably 0.5 to 3 equivalents, relative to the compound represented by I). The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but preferably,
Halogenated hydrocarbons (eg methylene chloride, chloroform), ethers (eg dioxane, tetrahydrofuran, 1,2-dimethoxyethane etc.), dimethylformamide and the like are used. These solvents can be used alone or in combination. Further, if necessary, a tertiary amine such as pyridine, collidine, lutidine, triethylamine and diisopropylethylamine may be added as a base to the reaction solvent. Reaction temperature is -50 ° C
To 100 ° C, preferably 20 ° C to 50 ° C. The reaction time is about 0.5 to 30 hours. The compound obtained by this reaction is purified by a general method such as recrystallization, reprecipitation or column chromatography after removing the reaction solvent by a conventional method. The substituents on the compounds obtained by this method may be modified by conventional methods and converted to compounds covered by formula (I).

Formula (II) used as a raw material in the above reaction
The compound represented by can be produced by a known method. For example, retinoyl fluoride used as a raw material in Examples 1 and 2-1 below is
Arun B. Barua and James A. Olson, Bio Kimika Eto
Biochijica et Biophysic
a Acta) 757 , 288-295 (1983). Further, the compound represented by the formula (IV) can also be produced by a known method. For example, L-ascorbic acid 5,6-acetonide used as a raw material in Example 1 below can be obtained from Chung Chen Wei et al., Journal of Organic Chemistry, 5.
0, it is prepared by methods which are reported in 3462-3467 (1985).

The compound represented by the formula (I) of the present invention has an antioxidant action and is useful as an antioxidant for foods, for example.

[0040]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Example 1 3-retinoyl L-ascorbic acid 5,6-acetonide L-ascorbic acid 5,6-acetonide 453 mg (2.
To 3 ml of a pyridine solution of 1 mmol) was added 7 ml of a methylene chloride solution of 290 mg (0.96 mmol) of retinoyl fluoride, and the mixture was stirred at room temperature for 15 hours for reaction. The reaction solution is diluted with ethyl acetate and washed successively with diluted hydrochloric acid and water. After drying over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was subjected to column chromatography (silica gel, eluent).
Ethyl acetate: hexane = 2: 3) to give 3-retinoyl L-ascorbic acid 5,6-acetonide 28
0 mg (59% yield) was obtained as a yellow oil. The resulting compound exhibited antioxidant properties. MS m / z: 498.263 (M ⁺ , C ₂₉ H ₃₈ O ₇ ) IR (CHCl ₃ ) cm ⁻¹ : 3540, 3280, 1780,
1720 (sh), 1705, 1600, 1565 UV (EtOH) λ: 365 nm ¹ H-NMR (CDCl ₃ ) δ: 1.04 (6 H, s, 1'-gem-
Me), 1.37, 1.40 (3H, s, OCMe ₂ C respectively)
O), 1.73 (3H, s, 5'-Me), 2.05 (3H, s, 9 '
-Me), 2.44 (3H, s, 13'-Me), 4.07, 4.1
8 (each 1H, dd, J = 8,7Hz, 6-H 2), 4.35
(1H, td, J = 7,2.5Hz, 5-H), 4.75 (1H, d,
J = 2.5 Hz, 4-H), 5.88 (1 H, br s, 14'-
H), 6.19 (1H, d, J = 16Hz, 8'-H), 6.20
(1H, brd, J = 11.5Hz, 10'-H), 6.35 (1
H, d, J = 15Hz, 12'-H), 6.41 (1H, brd, J
= 16 Hz, 7'-H), 7.22 (1H, dd, J = 15,11.
5Hz, 11'-H), 7.94 (1H, brs, 2-OH)

Example 2-1 3-retinoyl L-ascorbate Retinoyl fluoride 304 mg (1.01 mmol) and sodium L-ascorbate 304 mg (1.54 mmol)
7 ml of the dimethylformamide solution of 1 is reacted with stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (Cosmosil).
140C ₁₈ -opn, eluent tetrahydrofuran: acetonitrile = 1: 9) as eluant to afford 3-retinoyl L- ascorbic acid 396mg (86% yield) as pale yellow crystals. The resulting compound exhibited antioxidant properties. MS m / z: 458.231 (M +, C 26 H 34 O 7) IR (CHCl 3) cm -1: 3600-3150,1775,
1720, 1705, 1600, 1565 UV (EtOH) λ: 365 nm ¹ H-NMR (CDCl ₃ ) δ: 1.04 (6H, s, 1′-gem-
Me), 1.73 (3H, s, 5'-Me), 2.05 (3H, s, 9 '
-Me), 2.43 (3H, s, 13'-Me), 3.83 (1H, d
d, J = 11.5Hz, 6-H), 3.89 (1H, dd, J = 1)
1.6 Hz, 6-H), 4.00 (1 H, m, 5-H), 4.90
(1H, d, J = 2Hz, 4-H), 5.88 (1H, brs, 14 '
-H), 6.18 (1H, d, J = 16Hz, 8'-H), 6.1
9 (1H, brd, J = 11.5Hz, 10'-H), 6.34
(1H, d, J = 15Hz, 12'-H), 6.39 (1H, br d,
J = 16Hz, 7'-H), 7.21 (1H, dd, J = 15,1)
1.5Hz, 11'-H), 7.80-8.10 (1H, br, O
H).

Example 2-2 3-retinoyl L-ascorbic acid 280 mg of 3-retinoyl L-ascorbic acid 5,6-acetonide obtained in Example 1 was dissolved in 4 ml of a solution of tetrahydrofuran: methanol = 3: 1. 1.2 ml of 2N hydrochloric acid was added and the reaction was carried out at 50 ° C. for 1.5 hours with stirring.
The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue obtained was subjected to thin layer chromatography (RP-18, Merck Art. 1).
Purification using 5389, solvent, tetrahydrofuran: acetonitrile = 1: 9) gave 76 mg (yield 70%) of 3-retinoyl L-ascorbic acid as pale yellow crystals. The resulting compound exhibited antioxidant properties. MS m / z: 458.231 (M +, C 26 H 34 O 7) IR (CHCl 3) cm -1: 3600-3150,1775,
1720, 1705, 1600, 1565 UV (EtOH) λ: 365 nm ¹ H-NMR (CDCl ₃ ) δ: 1.04 (6H, s, 1′-gem-
Me), 1.73 (3H, s, 5'-Me), 2.05 (3H, s, 9 '
-Me), 2.43 (3H, s, 13'-Me), 3.83 (1H, d
d, J = 11.5 Hz, 6-H), 3.89 (1 H, dd, J = 11.
6Hz, 6-H), 4.00 (1H, m, 5-H), 4.90 (1
H, d, J = 2Hz, 4-H), 5.88 (1H, brs, 14'-
H), 6.18 (1H, d, J = 16Hz, 8'-H), 6.19
(1H, brd, J = 11.5Hz, 10'-H), 6.34 (1
H, d, J = 15 Hz, 12'-H), 6.39 (1H, br d, J
= 16 Hz, 7'-H), 7.21 (1H, dd, J = 15,11.
5Hz, 11'-H), 7.80-8.10 (1H, br, OH).

[0043]

INDUSTRIAL APPLICABILITY According to the present invention, there are provided a novel compound useful as an antioxidant for foods and the like, an ester compound comprising retinoid and ascorbic acid, a derivative thereof and a method for producing them.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Hiroaki Kusaka 3-chome 1-32 Akura Minami, Takarazuka City, Hyogo Prefecture 1-202 (72) Inventor Yoshihiro Yamamoto 8-21 21 Ogino City, Itami City, Hyogo Prefecture 203 High Mind 203 issue

Claims (8)

[Claims] 1. Formula (I): [Wherein R ₁ is (X ₁ and X ₂ are the same or different and are an alkyl group,
A hydroxyalkyl group or a carboxyl group is shown. ) And R ₂ , R ₃ and R ₄ are the same or different and each represents hydrogen or an organic residue. Further, R ₃ and R ₄ may be taken together to form an acetal or a ketal. Furthermore, n is 1 to 10, and the inside of [] includes all stereoisomers. ] The compound or its salt represented by these. 2. The compound according to claim 1, wherein R ₂ , R ₃ and R ₄ are hydrogen, or a salt thereof. 3. R ₂ , R ₃ and R ₄ are each selected from an optionally substituted alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aralkyl group, aryl group, heterocyclic group or acyl group. The compound or salt thereof according to claim 1, which is an organic residue. 4. X ₁ and X ₂ are the same or different,
The compound or a salt thereof according to claim 1, which is a methyl group, a hydroxymethyl group or a carboxyl group. 5. R ₁ is The compound or salt thereof according to claim 1, which is a group represented by: 6. The compound according to claim 1, wherein n is 1 to 5, or a salt thereof. 7. The compound according to claim 6, wherein n is 2, or a salt thereof. 8. Formula (II): [In the formula, R ₁ has the same meaning as in the general formula (I), R ₅ represents halogen or the formula (III): (X ₅ represents an optionally substituted linear or branched alkyl group having 1 to 4 carbon atoms), n is 1 to 10, and [] The term includes all stereoisomers. ] And a compound of formula (IV) [Wherein R ₂ , R ₃ and R ₄ have the same meanings as in formula (I),
₃ and R ₄ may together form an acetal or ketal. R ₆ represents hydrogen, an alkali metal or an alkaline earth metal. ] The compound represented by the formula (I) characterized by reacting: [Wherein R ₁ is (X ₁ and X ₂ are the same or different and represent an alkyl group, a hydroxyalkyl group, or a carboxyl group), and R ₂ , R ₃ and R ₄ are the same or different and each represent a hydrogen atom or an organic residue. Show. Further, R ₃ and R ₄ may be taken together to form an acetal or a ketal. Furthermore, n is 1 to 10, and the inside of [] includes all stereoisomers. ] The manufacturing method of the compound represented by these.